CN103585179A - Pharmaceutical composition and application thereof in preparation of drug for treating bone marrow hematopoietic function disorder - Google Patents
Pharmaceutical composition and application thereof in preparation of drug for treating bone marrow hematopoietic function disorder Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition, comprising the medicinal ingredients of mesenchymal stem cells (MSCs) of expressing SDF-1/HOXB4 fusion gene and CD34<+> hematopoietic stem cells (HSCs). An adenoviral expression vector is built by the invention; the SDF-1, HOXB4 and fuse protein SDF-1/HOXB4 thereof are respectively expressed; the effects of cotransplantation of the mesenchymal stem cells of expressing the SDF-1/HOXB4 fusion gene combined with the fetal blood CD34<+> hematopoietic stem cells on radiation-injured mice are observed. The result shows that hematopoietic reconstitution and implantation can be facilitated by cotransplantation of the mesenchymal stem cells (MSCs) of expressing the SDF-1/HOXB4 fusion gene combined with the fetal blood CD34<+> hematopoietic stem cells (HSCs), and the success rate of transplantation is also improved.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, particularly a kind of medicine for the treatment of hemopoietic function of bone marrow disorder disease.
Background technology
It is one of the hemopoietic function of bone marrow obstacle that causes for the treatment of hematopathy, malignant solid tumor chemicotherapy and the effective ways of multiple ischemia anemi (Borhane G that hematopoietic stem cell (Hematopoietic Stem Cells, HSCs) is transplanted; Mickie B.Transplantation of human hematopoietic repopulating cells:mechanisms of regeneration and differentiation using human-mouse xenografts.Current Opinion in Organ Transplantation.2008; 13 (1): 44-52.).But the rear HSCs of transplanting goes back to the nest, rate is low, and self duplication is limited in one's ability, becomes the bottleneck problem of restriction Hemopoietic Reconstruction In Bone Marrow.In recent years; along with people are to mesenchymal stem cells MSCs (mesenchymal stem cells; MSCs) basis and clinical progress; much studies confirm that MSCs and HSCs combined transplantation can promote implantation and hematopoietic reconstitution (the Fliedner TM of hematopoietic stem cell; Powles R; Sirohi B, et al.Radiologic and nuclear events:the METREPOL severity of effect grading system.Blood.2008; 111 (12): 5757-8; Isern J, Martin-Antonio B, Ghazanfari R, et al.Self-Renewing Human Bone Marrow Mesenspheres Promote Hematopoietic Stem Cell Expansion.LID-S2211-1247 (13) 00165-4[pii] LID-10.1016/j.celrep.2013.03.041[doi] .Cell Rep.2013; Isern J, Martin-Antonio B, Ghazanfari R, et al.Self-Renewing Human Bone Marrow Mesenspheres Promote Hematopoietic Stem Cell Expansion.LID-S2211-1247 (13) 00165-4[pii] LID-10.1016/j.celrep.2013.03.041[doi] .Cell Rep.2013; Jia Xintao, Mu Yuanyuan, Jia Xiaoxiao etc. people's umbilical blood CD34
+cell is effective reconstitute hematopoiesis system [J] on NOD/SCID mice. Third Military Medical University's journal, 2011,33 (11); 1136-1140.).MSCs is as the energy selective attachment of hematopoieticmicroenviron-ment main cellular and support HSCs propagation and migration (Le Blanc K, Samuelsson H, Gustafsson B, et al.Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells.Leukemia.2007, 21 (8): 1733-8), chemotactic factor SDF-1 and receptor CXCR 4 thereof going back to the nest and implanting the effect of having played important adjusting HSCs in this process, the SDF-1 of MSCs high expressed can mediate HSCs propagation and migration, attract it to bone marrow, to return field planting (Broxmeyer HE, Hangoc G, Cooper S, et al.AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis.Ann N Y Acad Sci.2007, 1106:1-19.).Transcription factor HOXB4 is for regulating the balance between HSCs self renewal and differentiation to play an important role; can effectively strengthen HSCs self-renewal capacity (Lu SJ; Feng Q; Ivanova Y, et al.Recombinant HoxB4 Fusion Proteins Enhance Hematopoietic Differentiation of Human Embryonic Stem Cells.Stem Cells Dev.2007; 16 (4): 547-60; Bonde S, Dowden AM, Chan KM, et al.HOXB4 but not BMP4 confers self-renewal properties to ES-derived hematopoietic progenitor cells.Transplantation.2008; 86 (12): 1803-9; Tang Y, Chen J, Young NS.Expansion of haematopoietic stem cells from normal donors and bone marrow failure patients by recombinant hoxb4.Br J Haematol.2009; 144 (4): 603-12.).The MSCs of existing result of study prompting by proceeding to fusion gene is as feeder layer cells, and umbilical blood CD34 more effectively in vitro can increase
+cell, (wear, Chen Tingting, Ye Feng etc. the effect that the mescenchymal stem cell of expressing SDF-1/HOXB4 fusion gene maintains hematopoietic stem cell population and dryness. the journal .2013.35(7 of Third Military Medical University) .589-594.).But HOXB4 crosses high expressed as transcription factor and may impact cell other biological aspect, the expression that improves HOXB4 can strengthen CD34
+the propagation of cell and self renewal, meanwhile also weakened cell short-term differentiation capability (Zhong Bo, Ye Feng, Wang Tao etc. the clone of the survivin promoter gene fragment of different activities and evaluation [J]. Third Military Medical University's journal, 2011,33 (11): 1115-1118; Bell E.Transplantation:Making space for HSCs.Nature Biotechnology.2008; 8 (1): 4-5).So whether fusion gene can impact hematopoietic cell self-characteristic or differentiation capability, whether can also bring into play in vivo said function and also need further research.
Summary of the invention
The present invention has taken into account " chemotactic identification " and " self renewal " in hematopoieticmicroenviron-ment process of reconstruction, after the specificity of ligand receptor combination is promoted to radiation with cellular replacement therapy, hematopoietic reconstitution combines, built adenovirus expression carrier, express respectively SDF-1, HOXB4 and fusion protein S DF-1/HOXB4 thereof, observe the mesenchyma stem cell combined umbilical blood CD34 that expresses SDF-1/HOXB4 fusion gene
+the impact of stem cell co-transplantation on irradiated mice, result shows to express mescenchymal stem cell (MSCs) the associating umbilical blood CD34 of SDF-1/HOXB4 fusion gene
+hematopoietic stem cell (HSCs) co-transplantation can promote hematopoietic reconstitution and implantation, improves transplanting succeed rate.
, its active ingredient is by the mescenchymal stem cell (MSCs) and the CD34 that express SDF-1/HOXB4 fusion gene
+hematopoietic stem cell (HSCs) forms.
The mescenchymal stem cell (MSCs) and umbilical blood CD34 of described expression SDF-1/HOXB4 fusion gene
+the cell amount ratio of hematopoietic stem cell (HSCs) is 8:1.
Described CD34
+derived from hematopoietic precursor cells is in umbilical blood.
The application of aforementioned pharmaceutical compositions in the medicine of preparation treatment hemopoietic function of bone marrow disorder disease.
Described hemopoietic function of bone marrow disorder disease is caused by radiation.
The present invention, by expressing 3 adenovirus vectors difference transfection Normal Human Bone Marrow MSCs of SDF-1, HOXB4 and SDF-1/HOXB4 gene, is combined umbilical blood CD34
+in the NOD/SCID Mice Body of radiation damage, (MSCs 8 * 10 through tail vein transplantation for cell
5individual cell/only, CD34
+1 * 10
5individual cell/only), be respectively SDF-1/MSCs+CD34
+group (SDF-1 group), HOXB4/MSCs+CD34
+group (HOXB4 group), SDF1-HOXB4/MSCs+CD34
+group (S-H group), other 3 groups is untransfected MSCs+CD34
+group (MSC-HSC group), simple CD34
+group (HSC group), simple irradiation group (IR group).After detecting transplanting, respectively organize mouse survival rate, peripheral hemogram recovery, bone marrow pathological change and people source CD45
+cell implantation rate.Result shows SDF-1 group, HOXB4 group, the hemopoietic of S-H group is suppressed organizes gently compared with IR, recovers fast, and survival rate is compared with IR group high (P<0.05).With the short hemopoietic restitution of S-H group, significantly strengthen, and after transplanting 6 weeks CD45
+cell implantation rate (47.43 ± 8.89%) is high compared with all the other groups.Mescenchymal stem cell (MSCs) the associating umbilical blood CD34 of SDF-1/HOXB4 fusion gene is expressed in this explanation
+hematopoietic stem cell (HSCs) co-transplantation can promote hematopoietic reconstitution and implantation, improves transplanting succeed rate.
Accompanying drawing explanation
Fig. 1 respectively organizes mice and transplants the observation of science of rear different time myelosis
Wherein: A-F is respectively IR group, HSC group, MSC-HSC group, SDF-1 group, HOXB4 group, S-H group transplanting rear the 14th day (* 400); G-K is respectively HSC group, MSC-HSC group, SDF-1 group, HOXB4 group, S-H group transplanting rear the 21st day (* 400)
Fig. 2. each organizes mouse bone marrow cells CD45
+cell proportion
The specific embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Materials and methods
1 carrier and reagent
PAD-SDF-1-IRES-EGFP, pAD-HOXB4-IRES-EGFP, pAD-SDF-1-(GlySer) the 3-HOXB4-IRES-EGFP adenovirus vector of expressing respectively SDF-1, HOXB4 and fusion protein S DF-1/HOXB4 thereof are built by applicant, can externally provide.Construction method see " wear, Chen Tingting, Ye Feng etc. the effect that the mescenchymal stem cell of expressing SDF-1/HOXB4 fusion gene maintains hematopoietic stem cell population and dryness. the journal .2013.35(7 of Third Military Medical University) .589-594. "
Culture medium DMEM+10% hyclone is purchased from Invitrogen company, and MACS Magnetic Isolation test kit is purchased from Miltenyi company, and the mouse-anti people CD45 of FITC labelling and contrast IgG2b, IgG1 be purchased from BD company, lymphocyte separation medium TBD company.
1.2 laboratory animals and Specimen origin
118 of NOD/SCID female mices, 8～10 weeks, body weight was about 18～22g, purchased from Third Military Medical University's Experimental Animal Center.People's umbilical blood is taken from the court's department of obstetrics and gynecology healthy pregnant women full-term normal delivery infant umbilical cord, everyone collection capacity 60～90ml.Bone marrow is taken from the outpatient service bone marrow examination of the court hematology without patients with abnormal, and everyone gathers 2～4ml.All collection of specimens Jun Huo Hospital Ethical Committee's approvals and patient and family members agree to.
1.3 Cell isolation and culture
It is separated that mesenchymal stem cells MSCs is pressed density－gradient centrifuga－tion method, method see (
jung S,
panchalingam KM,
rosenberg?
l.et al.Ex vivo expansion of human mesenchymal stem cells in defined serum-free media ［ J ］ .Stem Cells International.Volume 2012 (2012), doi:10.1155/2012/123030. clock ripple, Ye Feng, Wang Tao etc. the clone of the survivin promoter gene fragment of different activities and evaluation [J]. Third Military Medical University's journal, 2011,33 (11): 1115-1118. was cultured to for the 3rd generation, counted standby after 0.25% trypsinization.People's umbilical blood specimen is carried out to mononuclearcell separation according to bone marrow density－gradient centrifuga－tion method, utilize MASC magnetic bead system to carry out CD34
+cell purification, it is standby that cell is crossed post 2 times.(method detailed of above-mentioned Cell isolation and culture see " wear; Chen Tingting, Ye Feng etc. the effect that the mescenchymal stem cell of expressing SDF-1/HOXB4 fusion gene maintains hematopoietic stem cell population and dryness. the journal .2013.35(7 of Third Military Medical University) .589-594. ")
1.4 experiment packet design
All mices are accepted 60Co gamma-rays 3.5Gy whole body irradiation, and mice is divided into according to each 12 of every group of completely randomized designs: 1. SDF-1/MSCs+CD34
+group (SDF-1 group): input respectively SDF-1/MSCs (8 * 10 through tail vein in 12 hours after irradiation
5individual cell/only), CD34
+cell (1 * 10
5individual cell/only); 2. HOXB4/MSCs+CD34
+group (HOXB4 group): HOXB4/MSCs (8 * 10
5individual cell/only), CD34
+cell (1 * 10
5individual cell/only); 3. SDF1-HOXB4/MSCs+CD34
+group (S-H group): SDF1-HOXB4/MSCs (8 * 10
5individual cell/only), CD34
+cell (1 * 10
5individual cell/only); 4. common MSCs+CD34
+group (MSC-HSC group): untransfected MSCs (8 * 10
5individual cell/only), CD34
+cell (1 * 10
5individual cell/only); 5. simple CD34
+group (HSC group): CD34+ cell (1 * 10
5individual cell/only); 6. simple irradiation group (IR group), 0.3ml normal saline.
1.5 dynamically observe mice general status and hemogram, myeloid tissue recovery situation
Observation was respectively organized the situations such as mice (n=12) appearance, energy, diet, defecation and measured weight every day, and survival rate respectively organized in record.After transplanting, within the 7th, 14,21,28 days, respectively organize mice row docking blood sampling, measure leukocyte, hemoglobin and platelet levels.14th, 28 days each groups take off respectively 2 of neck execution mices, and row Wright's staining is observed medullary cell and learned variation.
1.6 flow cytometers detect mice people source CD45
+cell implantation rate
After transplanting, the 6th week de-neck put to death a mice, and normal saline is gone out mouse tibia, femur bone marrow.Prepare single cell suspension, after splitting erythrocyte, by CD45 antibody and the cell suspension lucifuge of mouse-anti people FITC labelling, hatch, flow cytometer detection after PBS washing.
1.7 statistical procedures
Measurement data with
represent, adopt the analysis of SPSS 21.0 statistical softwares, each time point physiochemical indice relatively adopts one factor analysis of variance, and homogeneity of variance is checked afterwards and adopted SNK methods analyst, heterogeneity of variance to check employing Games-Howell methods analyst afterwards.Each is organized survival rate and relatively adopts X 2 test.Test level P<0.05 has statistical significance.
2 results
1 general status is observed and mouse survival rate
Each is organized mice 24h after irradiation and all occurs in disorder by hair, movable minimizing, refusing to eat, and later body weight declines gradually.During extremely according to rear 21d, IR group mice is all dead.Transplant and respectively organize mice 7～10d after transplanting, activity, feed and amount of drinking water increase gradually, and weight starts to recover.To the 14th day, each organizes mouse survival rate difference statistical significance (P<0.05, table 1).Wherein, S-H group (100%), SDF-1 group (83%), HOXB4 group (75%) have statistical significance with IR group (25%) mouse survival rate difference, and S-H group has statistical significance (P<0.05, table 2) with HSC group, MSC-HSC group difference.To the 28th day, each is organized mouse death rate difference and still has statistical significance (P<0.05, table 1), wherein S-H group, SDF-1 group, HOXB4 group have statistical significance with IR group, HSC group mouse survival rate difference respectively, and S-H group has statistical significance (P<0.05, table 2) with MSC-HSC group mouse survival rate difference.
Table 1 is respectively organized the comparison of mouse survival rate
Table 2 is respectively organized mouse survival rate and is compared between two
2.2 peripheral blood hemogram detect
Each organizes mouse peripheral blood WBC and PLT sharply declines after irradiating 24 hours, within 7th～10 days, enters inhibitory stage.Except IR group is always in reduced levels, each organizes mouse peripheral blood WBC and all 14d left and right bottom outs after transplanting of PLT.S-H group is recovered respectively to organize time shorten compared with all the other with SDF-1 group WBC, at 21d, substantially recovers normal; MSC-HSC group is recovered normally at 28d substantially with HOXB4 group WBC, and HSC group is recovered normal (table 3) not yet completely at 28d.Except S-H group 28d peripheral blood PLT after transplanting recovers normally, all the other are respectively organized mice and all do not recover normal (table 4) completely at 28d.Each is organized mouse peripheral blood HGB 8th～12d after irradiation and enters inhibitory stage.IR group maintains reduced levels always, and all the other are respectively organized mouse peripheral blood HGB 18d left and right after transplanting and start rise to some extent, and except the 28d recovery after transplanting of S-H group is normal, all the other are respectively organized mice and all do not recover normal (table 5) completely at 28d.
Table 3 is respectively organized the comparison (n=5, x ± s) that mice is transplanted rear different time phases peripheral blood WBC
Table 4 is respectively organized the comparison (n=5, x ± s) that mice is transplanted rear different time phases peripheral blood HGB
Table 5 is respectively organized the comparison (n=5, x ± s) that mice is transplanted rear different time phases peripheral blood PLT
---: animal dead does not detect data; A, vs normal group, P<0.05; B, vsIR group, P<0.05;
2.3 myelosis are of science to be observed
Transplant latter the 14th day, IR group bone marrow sheet is oily outward appearance, is multiple location hypoplasia, and hematopoietic cell obviously reduces, and classification be take medullary system as main, and bone marrow granule is sky frame shape coarse net structure, cell rare (Figure 1A); All the other each groups all have hemopoietic in various degree to recover, bone marrow nucleated cell active proliferation, ratio increase, and SDF-1 group, HOXB4 group and S-H group recovery extent are better, and bone trabecula around visible fusiformis stromal cell is arranged, and with S-H, organizes the most obviously (Figure 1B-F).To transplanting latter the 21st day, it is normal that HSC group, MSC-HSC group, SDF-1 group and HOXB4 group are all recovered not yet completely, and effectively hemopoietic area is lower than S-H group (Fig. 1 G-J); And S-H group myelosis is obviously active, nucleated cell is a bunch shape and is clouded in medullary cavity, forms a plurality of newborn hemopoietic focus, megalokaryocyte a large amount of visible (Fig. 1 K).
Human specific CD45 in 2.4 Mice Bodies
+cell detection
The 6th week SDF-1 group, HOXB4 group and S-H group CD45 after transplanting
+cell percentage is apparently higher than HSC group, MSC-HSC group, and S-H group (47.43 ± 8.89%) higher than SDF-1 group, HOXB4 group (table 6, Fig. 2).
Table 6 is respectively organized mouse bone marrow cells CD45
+cell proportion
Conclusion
Adenovirus expression carrier transfection Normal Human Bone Marrow MSCs at SDF-1, HOXB4 for the application and SDF-1/HOXB4 fusion rotein, is combined umbilical blood CD34
+stem cell through tail vein co-transplantation in the Mice Body of radiation damage, the impact that then paired observation is rebuild irradiation damage mouse hemopoietic.Result shows, latter the 14th day of transplanting, and S-H group, SDF-1 group, HOXB4 group have statistical significance with IR group mouse survival rate difference, and S-H organizes and HSC group, MSC-HSC group difference have statistical significance (P<0.05, table 2).The last transplanting the 28th day, S-H group, SDF-1 group, HOXB4 group had statistical significance with IR group, HSC group mouse survival rate difference respectively, and S-H group has statistical significance (P<0.05, table 2) with MSC-HSC group mouse survival rate difference.Show that S-H group, SDF-1 group, HOXB4 group can increase the survival rate of irradiation mice, and higher than HSC group mouse survival rate, and S-H group mouse survival rate is higher than MSC-HSC group.Except IR group is always in reduced levels, each organizes mouse peripheral blood WBC and all 14d left and right bottom outs after transplanting of PLT.Wherein S-H group recovers fast compared with other each groups with SDF-1 group WBC, and S-H recovers normally substantially at 21d, and MSC-HSC group is recovered normally at 28d substantially with HOXB4 group WBC, and HSC group recovers normal not yet completely at 28d.Wherein S-H group 28d peripheral blood PLT after transplanting recovers normal, and all the other are respectively organized mice and all do not recover normal completely at 28d.Each is organized mouse peripheral blood HGB 18d left and right after transplanting and starts rise to some extent, and wherein S-H group 28d after transplanting recovers normal, and all the other are respectively organized mice and all do not recover normal completely at 28d.In conjunction with bone marrow, change prompting, S-H group, SDF-1 group, HOXB4 group mouse peripheral blood resemble the suppressed and myeloid tissue extent of damage and alleviate, and recover very fast, especially the most obvious with S-H group.S-H group may contribute to receptor hemogram and bone marrow smear after clinical transplantation to recover, and this points out us designed SDF-1/HOXB4 fusion rotein and CD34
+stem cell is to promoting the recovery of patient's hemopoietic function to have synergism.
CD45
+cell is the peculiar labelling of humanized's hematopoietic cell, can be different from mouse cell as the important indicator that detects hematopoietic cell implantation.We are the 6th week flow cytometer detection bone marrow CD45 after transplanting
+cell percentage, CD45 in S-H group mouse bone marrow cells
+cell percentage is apparently higher than all the other each groups (47.43 ± 8.89%), and prompting S-H group is implanted and had facilitation hematopoietic cell after transplanting, and guiding hematopoietic stem cell is gone back to the nest to bone marrow in Mice Body.
In sum, this experimental result confirms to express mescenchymal stem cell (MSCs) the associating umbilical blood CD34 of SDF-1/HOXB4 fusion gene
+hematopoietic stem cell (HSCs) co-transplantation can promote hematopoietic reconstitution and implantation, improves transplanting succeed rate.
Claims (5)
1. a pharmaceutical composition, its active ingredient is by the mescenchymal stem cell (MSCs) and the CD34 that express SDF-1/HOXB4 fusion gene
+hematopoietic stem cell (HSCs) forms.
2. pharmaceutical composition according to claim 1, the mescenchymal stem cell (MSCs) of described expression SDF-1/HOXB4 fusion gene and umbilical blood CD34
+the cell amount ratio of hematopoietic stem cell (HSCs) is 8:1.
3. pharmaceutical composition according to claim 1, described CD34
+derived from hematopoietic precursor cells is in umbilical blood.
4. the application of the arbitrary described pharmaceutical composition of claims 1 to 3 in the medicine of preparation treatment hemopoietic function of bone marrow disorder disease.
5. application according to claim 4, described hemopoietic function of bone marrow disorder disease is caused by radiation.
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Cited By (4)
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| CN105560571A (en) * | 2016-01-22 | 2016-05-11 | 詹林安 | Spine hematopoiesis patch and preparation method thereof |
| CN110613736A (en) * | 2019-10-30 | 2019-12-27 | 广州陈运贤生命科技有限公司 | Composition and preparation for treating bone marrow failure diseases, preparation method and application |
| CN113057968A (en) * | 2021-03-09 | 2021-07-02 | 吴皓宇 | Application of mesenchymal stem cells in preparation of medicine for preventing and treating radiation injury in cardiovascular interventional operation |
| CN113995773A (en) * | 2021-11-02 | 2022-02-01 | 中国医学科学院血液病医院(中国医学科学院血液学研究所) | Medicine for enhancing human hematopoietic stem cell transplantation ability and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105560571A (en) * | 2016-01-22 | 2016-05-11 | 詹林安 | Spine hematopoiesis patch and preparation method thereof |
| CN110613736A (en) * | 2019-10-30 | 2019-12-27 | 广州陈运贤生命科技有限公司 | Composition and preparation for treating bone marrow failure diseases, preparation method and application |
| CN113057968A (en) * | 2021-03-09 | 2021-07-02 | 吴皓宇 | Application of mesenchymal stem cells in preparation of medicine for preventing and treating radiation injury in cardiovascular interventional operation |
| CN113995773A (en) * | 2021-11-02 | 2022-02-01 | 中国医学科学院血液病医院(中国医学科学院血液学研究所) | Medicine for enhancing human hematopoietic stem cell transplantation ability and application thereof |
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